Modulatory action of dopamine on acetylcholine-responsive striatal and accumbal neurons in awake, unrestrained rats

In ambulant rats, iontophoresis of low concentrations of dopamine (DA) enhances the response of neurons in striatum and nucleus accumbens to iontophoretic glutamate. In an extension of this line of investigation, we tested the effects of acetylcholine (ACh), a presumed modulator of neuronal function in these same brain regions, and assessed possible DA-ACh interactions. Data were obtained from spontaneously active neurons known to respond to ACh (5–30 nA) when the animals rested quietly with no overt movement. ACh iontophoresis either excited or inhibited striatal and accumbal activity but excitatory effects predominated in both areas. With multiple applications of ACh, especially at the lowest currents tested, either response often was interspersed with instances of no change in firing rate. Responsiveness to ACh also diminished during periods of spontaneous movement when basal firing showed phasic increases in activity. In fact, neurons with the highest rates of basal activity showed the smallest magnitude response to ACh. Prolonged applications (120–180 s) of DA attenuated basal firing as well as the iontophoretic effects of ACh both during the DA application itself and for up to 1 min after DA ejection offset. The result of these inhibitory effects was no net change in the relative magnitude of the ACh response. Thus, although ACh can modulate striatal and accumbal neuronal activity, DA does not regulate this effect in the same way that it regulates the neuronal responsiveness to glutamate.     

左旋千金藤啶碱对外周血管多巴胺DA_1和DA_2受体亚型的作用

用家兔离体血管环方法，研究左旋千金藤啶碱（ｌＳＰＤ）对外周血管ＤＡ１和ＤＡ２受体亚型的作用。结果表明，ｌＳＰＤ使ＤＡ１受体激动剂ＦＯＤＡ诱发的肾、肺和肠动脉以及ＤＡ２受体激动剂ＰＢＤＡ诱发的肠和股动脉舒张反应的量效曲线非平行右移，最大反应（Ｅｍａｘ）降低，均呈非竞争性拮抗；ｌＳＰＤ本身还可使肾和肺血管产生轻度的浓度依赖性舒张反应，表现为ＤＡ１受体激动剂的作用特性。提示ｌＳＰＤ为外周血管ＤＡ１和ＤＡ２受体的混合性阻滞剂并兼有ＤＡ１受体部分激动剂的双重作用特性。     

Aromaticl-amino acid decarboxylase immunoreactive cells in the rat striatum: a possible site for the conversion of exogenousl-DOPA to dopamine

The efficacy ofl-dihydroxyphenylalanine (l-DOPA) in ameliorating the symptoms of Parkinson's disease (PD) is attributed to its conversion to dopamine (DA) by the enzyme aromaticl-amino-acid decarboxylase (AADC) in the striatum. Although the site of this conversion in the DA-denervated striatum has yet to be identified, it has been proposed thatl-DOPA could be converted to DA at non-dopaminergic sites containing AADC. In the present study, we used immunocytochemical techniques to examine the localization of AADC and DA in the striatum of rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal dopaminergic projection. In the DA-denervated striatum, we observed AADC-immunoreactive (-IR) cells with morphological characteristics similar to a class of small aspiny interneuron. Although usually obscured by a dense plexus of AADC-IR fibers, these cells could also occasionally be detected in the intact striatum. Acute administration of L-DOPA to DA-denervated animals elicited contralateral rotational behavior as well as a pronounced c-fos protein immunoreactivity in the striatum ipsilateral to the lesion. Following acute administration ofl-DOPA, but not after acute saline, DA-IR cells were detected in the denervated striatum. These DA-IR cells are similar in morphology and were found in the same location as the AADC-IR cells. These results strongly suggest the existence of a class of AADC-containing striatal cells that can form DA from exogenousl-DOPA in the rat. In the DA deafferented striatum, DA produced by these cells from exogenousl-DOPA could be released to exert physiological effects on DA receptive tissue. It is possible that similar cells could contribute to the efficacy ofl-DOPA in the treatment of Parkinson's disease.     

Characterisation of dopamine receptors in insect (Apis mellifera) brain

In vitro binding experiments using the vertebrate D₁ dopamine receptor ligand [³H]SCH23390 and the vertebrate D₂ dopamine receptor ligand [³H]spiperone were conducted on membrane preparations of honey bee (Apis mellifera) brain. Specific binding of [³H]SCH23390 was saturable and reversible. Analysis of saturation data gave an apparent K_d of 6.3 ± 1.0 nM and B_max of 1.9 ± 0.2 pmol/mg protein for a single class of binding sites. The specificity of high affinity [³H]SCH23390 binding was confirmed in displacement experiments using a range of dopaminergic antagonists and agonists. The rank order of potency for antagonists was: R(+)-SCH23390 > cis-(Z)-flupentixol ≥ chlorpromazine > fluphenazine> S(+)-butaclamol > spiperone. R(±)-SKF38393 and dopamine were the most effective agonists tested. [³H]SCH23390 labels a site in bee brain that is similar, but not identical to the vertebrate D₁ dopamine receptor subtype. [³H]Spiperone also bound with high affinity to bee brain homogenates. Scatchard analysis of [³H]spiperone saturation data revealed a curvilinear plot suggesting binding site heterogeneity. The high affinity site had a apparent K_d of 0.11 ± 0.02 nM and B_max of 9.2 ± 0.5 fmol/mg protein. The calculated values for the low affinity site were a K_d of 19.9 nM and B_max of 862 fmol/mg protein. Kinetic analyses also indicated that [³H]spiperone recognises a heterogeneous population of sites in bee brain. Furthermore, agonist competition studies revealed a phenolaminergic as well as a dopaminergic component to [³H]spiperone binding in bee brain. The rank order of potency of dopaminergic antagonists in competing for [³H]spiperone binding was: spiperone > fluphenazine> S(+)-butaclamol > domperidone> R(+)-SCH23390 > S(−)-sulpiride.     

Selective dopamine D4 receptor antagonists reverse apomorphine-induced blockade of prepulse inhibition

 Recent evidence suggests that the dopamine D₄ receptor may play a role in schizophrenia, and that the atypical properties of the antipsychotic clozapine may be attributable in part to its antagonistic actions at this receptor. In the present study, clozapine and three other compounds having D₄ dopamine receptor antagonist properties were examined for their effectiveness in reducing losses in prepulse inhibition (PPI) induced in rats by the dopamine receptor agonist apomorphine. Previously, activity in the PPI model has been shown to correlate highly with the antipsychotic potency of a number of neuroleptics. As previously reported, clozapine (1–5.6 mg/kg) significantly reduced apomorphine-induced PPI deficits. The three D₄-selective compounds, CP-293,019 (5.6–17.8 mg/kg), U-101,387 (3–30 mg/kg) and L-745,870 (1–10 mg/kg), also significantly blocked the losses in PPI produced by apomorphine. Taken together, these results suggest that dopamine receptor antagonists with selectivity for the D₄ dopamine receptor subtype may be effective in the treatment of schizophrenia, while being less likely to produce dyskinesias associated with D₂ receptor antagonists. Received: 13 May 1997/Final version: 15 July 1997     

Upregulation of striatal D2 receptors in the MPTP-treated vervet monkey is reversed by grafts of fetal ventral mesencephalon: an autoradiographic study

Although neural transplantation holds promise as a treatment for Parkinson's disease, parkinsonian primates have generally exhibited inconsistent and incomplete recovery of motor functions following intrastriatal grafting of fetal ventral mesencephalon. One possible contributing factor to this variable response is lack of appropriate integration of donor neurons with host striatal circuitry with the result that there is insufficient dopamine release and postsynaptic dopamine receptor activation. This issue was examined by measuring the effect of transplanting fetal ventral mesencephalon to the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated (MPTP) monkeys on striatal D2 receptor binding. One year after receiving MPTP, D2 receptor binding was upregulated in the dorsal and ventral striatum of African green monkeys. Grafting of fetal ventral mesencephalon to the dorsal striatum of MPTP-treated monkeys 9 months before sacrifice, eliminated the D2 receptor upregulation in dorsal, but not ventral, region. Dopamine concentration in dorsal striatum of grafted MPTP-treated monkeys was significantly higher than in that region of MPTP-treated non-grafted monkeys. In addition, dopamine concentration was significantly higher in dorsal compared to ventral striatum of grafted MPTP-treated monkeys. These data, in addition to those from a previous autoradiographic study on dopamine uptake site density in these monkeys, strongly supports the hypothesis that ectopically placed ventral mesencephalon not only produces, but maintains the release of sufficient levels of dopamine to restore postsynaptic dopamine transmission in regions influenced by graft-derived dopamine.     

Dopamine receptor antagonist blocks the release of glycine, GABA, and taurine produced by amphetamine

The effects of systemic injections of amphetamine sulfate on the extracellular levels of glycine, GABA, and taurine in the neostriatum of awake rats were studied using a push-pull perfusion system. Amphetamine produced a dose-related increase in glycine levels. Amphetamine also produced an enhancement on GABA and taurine levels, although these increases did not follow a dose-related curve. The percentage increase of amino acids produced by the highest dose of amphetamine (5 mg/kg) at the peak effect was: GLY 235.9%; GABA 218%, and TAU 177%. All these effects were blocked by the D1–D2 dopamine receptor antagonist, haloperidol. It is suggested that dopamine, released by amphetamine, induces the release of inhibitory amino acid neurotransmitters in the neostriatum. These results are consistent with the hypothesis of dopamine playing a role of an amplifier of the activity of different neurochemical circuits. The results are also in accord with the idea that dopamine could mediate the neurotoxic effects produced by amphetamines through an interplay between excitatory and inhibitory amino acids.     

Histamine and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline are competitive inhibitors of debrisoquine 4-monooxygenase in rat liver

The effects of histamine and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline(salsolinol) on debrisoquine 4-monooxygenation, which is catalyzed by cytochrome P-450db1(CYP2D1) in rat liver microsomes, were studied. Both histamine and salsolinol competitively inhibited the activity of debrisoquine 4-monooxygenase (Ki=0.31 and 0.43 mM, respectively). These data demonstrate that histamine and salsolinol bind to the active site of CYP2D1, i.e. histamine and salsolinol have structures (molecular shape) corresponding to the active site of CYP2D1.     

Lipophilic metabolite of [123I]β-CIT in human plasma may obstruct quantitation of the dopamine transporter

I-123 or C-11 labelled 2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT) is a recently developed radioligand for the study of dopamine and serotonin reuptake sites in humans with single photon emission tomography (SPET) or positron emission tomography (PET). Determination of the radioligand metabolite pattern is fundamental for a quantitative analysis of radioligand binding. The metabolism of [¹²³I]β-CIT was determined by a gradient HPLC method in plasma samples of six human subjects. Two metabolites of [¹²³I]β-CIT were found, a polar and a lipophilic. At 4 h after [¹²³I]β-CIT injection the percentages of parent compound and polar and lipophilic metabolites were 23 ± 3% (mean ± SD), 33 ± 11%, and 44 ± 8%, respectively. The lipophilic metabolite might pass the blood-brain barrier and account for a fraction of free and nonspecifically bound radioactivity in brain. The existence of a lipophilic metabolite of [¹²³I]β-CIT may obstruct the use of simple ratio methods for quantitation of the dopamine transporter in brain. © 1995 Wiley-Liss, Inc.     

Monoaminergic activities in Lewy Body dementia: Relation to hallucinosis and extrapyramidal features

Summary Serotonergic (5-HT) and dopaminergic activities have been examined in Lewy Body Dementia (LBD) and compared with Parkinson's disease (PD) and Alzheimer's disease (AD). In the neocortex the LBD subgroup experiencing hallucinations was distinguised from the other categories by an increase in the 5HIAA:5HT ratio measured in frontal cortex and by the serotonergic (5-HIAA or 5-HIAA:5-HT): cholinergic (choline acetyltransferase) ratio in frontal and temporal cortex. In the neostriatum (caudate nucleus), loss of dopamine and increased HVA: dopamine ratio correlated with the reduction in substantia nigra neurons in LBD but not PD, despite the greater loss of neurones and dopamine and the higher dopamine turnover ratio in PD. LBD patients experiencing severe Parkinsonism as a result of neuroleptic treatment tended to have lower neuron counts, in combination with higher turnover ratios, than the remainder. Qualitative differences between LBD and PD included decreased cortical 5-HT turnover in PD compared with the increase in LBD. There were no significant changes in any parameter in AD, with the exception of a reduction in temporal cortex 5HIAA. The results suggest that although the neurochemical pathology of LBD and PD involves similar systems, the nature of the derangements differs sufficiently between the diseases to account for differences in symptomatology.